Alzheimer's Disease is a devastating neurodegenerative disorder which is characterized by dramatic personality changes and global cognitive decline. It currently affects approximately four million Americans, taking more than 100,000 lives each year. See, R. Tanzi et al., Genetica, 91, 255 (1993). As described by D. J. Selkoe, Neuron, 6, 487 (1991) and Z. S. Khachaturian, Arch. Neurol., 42, 1097 (1989), this disease is pathologically characterized by the degeneration of the basal forebrain cholinergic system and the deposit of amyloid plaques in the brain.
One approach to treating this disease is to restore the level of neurotransmitter acetylcholine, which is found to be lowered in brains of the Alzheimer's patients, by inhibiting acetylcholinesterase (AChE) with reversible inhibitors. One class of AChE inhibitors includes huperzine A and analogs thereof. See, for example, Kozikowski (U.S. Pat. No. 5,104,880). Another such AChE inhibitor 9-amino-1,2,3,4-tetrahydroacridine (THA, also known as tacrine or COGNEX) is currently a drug approved by the United States Food and Drug Administration for the palliative treatment of mild and moderate Alzheimer's Disease. See, K. L. Davis et al., Lancet, 345, 625 (1995). The structure of THA is depicted below. ##STR2## However, the use of THA is currently limited by its serious hepatoxicity. Therefore, there is a continuing need for AChE inhibitors which may be useful to treat Alzheimer's Disease, including analogs of THA exhibiting improved profiles of bioactivity, such as higher potency, and a lower incidence or intensity of side effects.